Project description:Whole genome microRNA microarray expression profiling was employed as a discovery platform to identify microRNAs dysregulated in end-stage idiopathic pulmonary arterial hypertension (IPAH) patients. Lung tissue from seven IPAH patients and eight failed donor controls were subjected to microarray screening. Twenty-one miRNAs were identified dyeregulated in IPAH patients compared to controls. In miRNA real-time PCR validation, 22 IPAH patients and 22 control subjects were enrolled, including the 7 IPAH and 8 controls in microarray screening. Expression levels of five miRNAs (let-7a-5p, miR-199a-3p, miR-199b-5p, miR-26b-5p and miR-27b-3p) were upregulated in technical validation. Tissue miRNA levels had positive correlation with pulmonary vascular remodeling and hemodynamic changes in IPAH patients compared to controls.
Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.